CXCR4 is a class A G-protein coupled receptor (GPCR) that can bind stromal-derived factor 1 (SDF-1 also known as CXCL12), a CXC chemokine. Chemokines are members of a gene family of cytokines that can promote inflammatory and immunological responses by effecting the recruitment of appropriate leukocyte populations. Although chemokines have been characterized as promoting directed migration of leukocytes, they can also have roles outside the hematopoietic compartment. CXCR4 can be expressed constitutively in normal tissue.
Class A GPCRs have been characterized structurally by seven membrane spanning helical domains, an extracellular amino terminus, and a carboxy terminus on the intracellular side of the membrane. The seven transmembrane (TM) domains appear to be joined by three extracellular (ECL) and three intracellular (ICL) loops. Some crystal structures of CXCR4 appear to be reported in Wu et al., Science, Vol. 330, pp. 1066-1071 (2010).
CXCR4 is a chemokine receptor and a natural ligand for CXCR4 is the chemokine CXCL12. It appears that CXCR4 can be expressed on the surface of breast cancer cells. And in some instances, CXCR4 can play a role in both angiogenesis and metastasis in several tumor types, including, but not limited to, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian, melanoma, renal cell carcinoma, hepatocellular carcinoma, breast, colon, lung, pancreatic, and prostate cancers. CXCR4 expression by the tumor cells appears to be involved in tumor cell migration and in homing of the neoplastic cells to sites where non-malignant stromal cells express CXCL12.
Accordingly, there exists a further need (1) for treatment of disease (e.g., cancer) with a composition that may target CXCR4 or a G-protein, (2) for modulation of activity of CXCR4 with a composition, and (3) for providing pharmaceutical compositions that may treat diseases related to CXCR4 or G-proteins. Some embodiments of the present invention may address one or more of these needs.